Glaucoma is the second leading cause of blindness in the world. With strong genetic components to glaucoma, more than a dozen mapped open-angle glaucoma loci and three identified open-angle glaucoma genes, the genetic causes of most cases of open- angle glaucoma have not yet been accounted for. New screening methods and early diagnosis could prevent irreversible damage that often occurs before open-angle glaucoma is diagnosed. Novel therapies are needed to help save sight for many who do not respond adequately to existing therapies. Our long-range goal is the elucidation of the underlying genetic components of glaucoma, critical information for the development of novel tests and therapies. This project will characterize two genomic regions in which we find genetic evidence of open-angle glaucoma genes, and identify and characterize those open-angle glaucoma genes. We will clone the gene located in a locus that we confirmed, the GLC1I locus, and study a syndromic glaucoma gene, LMX1B, that we have shown is associated with non-syndromic open-angle glaucoma at a statistically significant level. This study will take advantage of our experience with the proposed methodologies, our demonstrated ability to find disease genes, and our major collection of samples from individuals and families with open-angle glaucoma, including individuals and families that show evidence of linkage and/or association with markers in the regions we will study. This competing renewal of a successful project remains focused on the hunt for the open-angle glaucoma genes. Each new open-angle glaucoma gene becomes a powerful tool for the study of glaucoma and provides novel mechanistic insights as well as opportunities for advances in both translational work and basic science. Since only three of many open-angle glaucoma genes have been identified, identification of any new open-angle glaucoma genes will significantly advance the field. PUBLIC HEALTH RELEVANCE: This project will study two regions of the genome in which we see evidence of genes that can cause primary open-angle glaucoma (POAG). We will identify a new POAG gene through use of high-density screening of the region known to contain the gene. We will determine how a syndromic glaucoma gene that we cloned can play a role in non- syndromic forms of POAG and confirm that role through validation in a second population. Each new open-angle glaucoma gene identified becomes a powerful tool for the study of glaucoma and provides new insights into the underlying causes of disease as well as opportunities for advancements in terms of both clinical and basic science.